Isoquinolines And Beta-Carbolines As Neurotoxins And NeuroprotectantsNew Vistas In Parkinson's Disease Therapy /

X, 178 p.online resource

Tryprophan metbolism in alcoholism. Tryptophan but not excitatory amino acid availablity to the brain is increased before the appearance of the alcohol-withdrawal syndrome in men

Tryptophan (Trp) metabolism and disposition and excitatory and other amino acid concentrations were determined in alcohol-dependent subjects in relation to the alcohol-withdrawal syndrome (AWS). Parameters were examined in 12 alcohol-dependent male subjects, undergoing elective upper digestive tract tumour resection, and 12 age-, gender-, and medication-matched controls on three occasions: pre-operatively, post-operatively, and immediately before (i.e. within 24 h of) the appearance of the AWS. No significant differences were observed between controls and alcoholic subjects on the first or second ot these occasions. On the third occasion, within 24 h of the appearance of the AWS, alcoholics showed a dramatic elevation (117%) in free serum Trp concentration and a consequent increase (111%) in the ratio of [free Trp]/[competing ammo acids], which is an accurate predictor of Trp entry into the brain. Increases were also observed on this third occasion in concentrations of total Trp (49%), cortisol (123%), and norharman (137%). Concentrations of glutamate, glycine, aspartate, serine, and taurine did not differ significantly within or between the control and alcohol-dependent groups of subjects on any of the three occasions. The possible significance of the Trp and related metabolic changes in relation to the behavioural features of the AWS is discussed

A preoperative dose of the pyridoindole AC102 improves the recovery of residual hearing in a gerbil animal model of cochlear implantation

Abstract Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. In a gerbil animal model of CI, AC102 significantly improves the recovery of hearing thresholds across multiple frequencies and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. In vitro experiments in an ethanol challenged HT22 cell-line revealed significant and dose-responsive anti-apoptotic effects following the treatment of with AC102. Further, AC102 treatment resulted in significant downregulation of the expression of pro-inflammatory cytokines in an organotypic ex vivo model of electrode insertion trauma (EIT). These results suggest that AC102’s effects are likely elicited during the inflammatory phase of EIT and mediated by anti-apoptotic and anti-inflammatory properties, highlighting AC102 as a promising compound for hearing preservation during CI. Moreover, since the inflammatory response in CI shares similarities to that in other etiologies of SNHL, AC102 may be inferred as a potential general treatment option for various inner ear conditions